Stefanov Alex, Brakel Kiralyn, Rau Josephina, Joseph Rose M, Guice Corey, Araguz Kendall, Hemphill Annebel, Madry Jessica, Irion Andrew, Dash Swapnil, Souza Karienn A, Hook Michelle A
Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College of Medicine, Bryan, TX 77807; Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843.
Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, College of Medicine, Bryan, TX 77807; Texas A&M Institute for Neuroscience, Texas A&M University, College Station, TX 77843.
Brain Behav Immun. 2025 Jan;123:270-287. doi: 10.1016/j.bbi.2024.09.015. Epub 2024 Sep 15.
Depression and cognitive deficits present at higher rates among people with spinal cord injury (SCI) compared to the general population, yet these SCI comorbidities are poorly addressed. Sex and age appear to play roles in depression incidence, but consensus on the direction of their effects is limited. Systemic and cortical inflammation and disruptions in hippocampal neurogenesis have been identified as potential treatment targets, but a comprehensive understanding of these mechanisms remains elusive. We used a rodent SCI model to interrogate these gaps in knowledge. We examined post-injury depression-like behavior and cognitive deficits, as well as the association between affect, cognition, chronic hippocampal inflammation and hippocampal neurogenesis, in young and middle-aged male and female Sprague-Dawley rats. Depression-like behavior manifested in male and female subsets of SCI rats irrespective of age, at rates commensurate with the incidence of clinical depression. Changes in components of behavior were driven by sex and age, and affective outcomes were independent of common post-injury pathophysiological outcomes including locomotor functional deficits and spinal lesion severity. Interestingly, however, only male depression-like SCI rats exhibited deficits in hippocampal-associated spatial cognition. Neurogenesis was also disrupted in only SCI males in regions of the hippocampus responsible for affective outcomes. Decreased neurogenesis among middle-aged male subjects coincided with increases in numbers of the pro-inflammatory markers CD86 and iNOS, while middle-aged females had increased numbers of cells expressing Iba-1 and anti-inflammatory marker CD206. Overall, the present data suggest that post-SCI depression and cognition may be affected, in part, by sex- and age-dependent changes in hippocampal neurogenesis and inflammation. Hippocampal neurogenesis is a potential target to address psychological wellbeing after SCI, but therapeutic strategies must carefully consider sex and age as biological variables.
与普通人群相比，脊髓损伤（SCI）患者中抑郁症和认知缺陷的发生率更高，但这些SCI合并症却未得到充分治疗。性别和年龄似乎在抑郁症发病率中起作用，但关于它们影响方向的共识有限。全身和皮质炎症以及海马神经发生的破坏已被确定为潜在的治疗靶点，但对这些机制的全面理解仍然难以捉摸。我们使用啮齿动物SCI模型来探究这些知识空白。我们研究了年轻和中年雄性及雌性Sprague-Dawley大鼠损伤后的抑郁样行为和认知缺陷，以及情感、认知、慢性海马炎症和海马神经发生之间的关联。无论年龄大小，SCI大鼠的雄性和雌性亚组均表现出抑郁样行为，其发生率与临床抑郁症的发病率相当。行为成分的变化由性别和年龄驱动，情感结果独立于常见的损伤后病理生理结果，包括运动功能缺陷和脊髓损伤严重程度。然而，有趣的是，只有雄性抑郁样SCI大鼠在海马相关的空间认知方面表现出缺陷。神经发生也仅在负责情感结果的海马区域的SCI雄性大鼠中受到破坏。中年男性受试者神经发生减少与促炎标志物CD86和诱导型一氧化氮合酶（iNOS）数量增加同时出现，而中年女性表达离子钙接头蛋白1（Iba-1）和抗炎标志物CD206的细胞数量增加。总体而言，目前的数据表明，SCI后的抑郁和认知可能部分受到海马神经发生和炎症中性别和年龄依赖性变化的影响。海马神经发生是解决SCI后心理健康问题的一个潜在靶点，但治疗策略必须仔细考虑性别和年龄作为生物学变量。
